There is evidence to indicate that Phospholipase A2 (PLA2) is involved in the pathogenesis of many diseases. Thus local and circulating levels of Phospholipase A2 enzyme and enzymatic products are elevated during infection, inflammatory diseases, tissue injury and brain dysfunction and is a very early indication of neoplastic development prior to tumour cell mass being evident by conventional methods of scanning tissue tumours.
Excessive Phospholipase A2 activity may promote chronic inflammation, allergic reaction, tissue damage and pathophysiological complications. These effects may be the result of accumulating Phospholipase A2 products (lysophospholipids and free fatty acids, e.g. Arachidonic Acid) and destruction of key structural phospholipid membrane components, but are potentated by secondary metabolites, such as eicosanoids and platelet-activating factor. Phospholipase A2 products or lipid mediators derived therefrom have been implicated in numerous activities that are an integral part of cell activation; chemotaxis, adhesion, degranulation, phagocytosis and aggregation.
Phospholipase A2 secreted excessively at local sites may be responsible for tissue damage common to rheumatic disorders, alveolar epithelial injury of lung disease and reperfusion.
During acute myocardial ischemia, cytosolic Phospholipase A2 and Phospholipase C activation causes increased intracellular Ca2+. Subsequent accumulation of lysophospholipids and free fatty acids promote damage to sarcolemmal membranes leading to irreversible cell injury and eventually cell death.
Altered cytosolic Phospholipase A2 and Phospholipase C activity or defects in their control and regulation is a predisposing factor to causing tumour cell development.
Prostaglandins and related eicosanoids are important mediators and regulators of both immune and inflammatory responses. Prostaglandin E2 induces bone resorption and Leukotriene B4 stimulates vascodilation and chemotaxis. Increased levels of Phospholipase A2 is noted in Rheumatoid Arthritis (R.A.), osteoarthritis, gout, collagen and vascular diseases. Phospholipase A2 induces non specific airway hyperactivity that is evident in asthma. Phospholipase A2 is also elevated in peritonitis, septic shock, renal failure, pancreatis, Chrons and Graves Disease.
The activity of cell-mediated defence systems is stimulated by consecutive formation of interleukin 1β(IL-1β), interleukin-2 (IL-2) and interferon γ (IFN γ). The system is inhibited by interleukin-4 (IL-4) and also by prostaglandin E2, (PGE2) and histamine, which are released when the immune system is activated. The inhibition is strong in cancer patients, because PGE2 is formed in many cancer cells and its formation is stimulated by IL-1β. PGE2 and histamine are feedback inhibitors of cell mediated immunity.
PGE2 is formed from arachidonic acid in monocytes, macrophages, cancer cells and other cells, when arachidonic acid is released from cellular phospholipids. The formation of PGE2 is stimulated by several compounds, including histamine, IL-1 (α and β) and Tumour Necrosis Factor α (TNFa). PGE2 inhibits the formation and receptor expression of IL-2 by increasing the level of cyclic AMP (cAMP) in helper T cells. This concomitantly decreases the formation of IFNγ.
PGE2 inhibits the ability of natural killer cells (NK) to bind with tumour cells by increasing cAMP in Natural Killer Cells. This decreases tumour cell killing.
When the immune system is stimulated to destroy tumour cells, the killing is prevented because IL-1β stimulates PGE2 formation in tumour cells, which increases cAMP levels in NK cells and prevents the binding of NK and tumour cells.
The activation of the cell-mediated defence is blocked also because PGE2-increases cAMP in helper T cells and inhibits the formation of IL-2 and IFNγ.
Cytotoxic T cells can also produce PGE2 thus inhibiting the activity of NK cells.
A number of human and experimental animal tumours, contain and/or produce large quantities of prostaglandins (PG). Prostaglandins E2 has been shown to effect significant cell proliferation in tumour growth and to suppress immune responsiveness.
Phosphatidylinositol specific phospholipase C is an important enzyme for intracellular signalling. There are at least three major classes of Phosphatidylinositol specific Phospholipase C (PtdlnsPLC: PtdlnsPLC β, γ, δ). PtdlnsPLCs hydrolyse a minor membrane phospholipid, phosphatidylinositol (4, 5) bisphosphate (Ptdlns (4,5) P2) to give the second messengers inositol (1, 4, 5) trisphosphate (Ins (1, 4, 5) P3), which releases Ca++ from intracellular stores to increase the intracellular free CA++ concentration, and diacylglycerol which activates the Ca++ and phospholipid-dependent protein serine/threonine kinase, protein kinase C. Proteins phosphorylated by protein kinase C include transcription factors. Together, the increase in intracellular free Ca++ concentration and the activation of protein kinase C lead to a series of events that culminate in DNA synthesis and cell proliferation in tumour cells.
A number of growth factors and mitogens, including platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and bombesin, act through specific receptors to increase Ptd lns PLC activity in cells. Continued stimulation of Ptd Ins PLC can lead to cell transformation.
Ptd Ins PLC activity is found to be increased in a number of human tumours. 76% of human breast cancers have detectable Ptd Ins PLC-γ immunoreactive protein compared to only 6% in benign breast tissue.
Cytosolic Ptd lns PLC activity is increased up to >4-fold in human non-small cell lung cancer and renal cell cancer compared to normal tissue.